Bisphosphonate Formulation

ABSTRACT

A bisphosphonate is formulated with an agent to reduce surface tension and/or reduce foaming in the stomach, leading to reduced reflux and oesophageal irritation in use and increased patient compliance.

FIELD OF THE INVENTION

The present invention relates to formulations comprising bisphosphonatesand their use in treatment of various conditions, especially suchformulations for treatment of osteoporosis.

BACKGROUND TO THE INVENTION

Osteoporosis is a disease of bone in which the amount of bone isdecreased and the strength of trabecular bone is reduced, cortical bonebecomes thin and bones are susceptible to fracture.

It is estimated that 10 million Americans have established osteoporosisand another 34 million have osteopenia, or low bone mass, which leads toosteoporosis. The disease is responsible for 1.5 millions fracturesannually, mostly involving the lumbar vertebrae, hip, and wrist.

Patients who are at risk for osteoporosis can be treated with vitamin Dand calcium supplements. Bisphosphonates are also commonly used in theprophylaxis and treatment of osteoporosis and corticosteroid-inducedosteoporosis. Bisphosphonates are synthetic analogues of naturalpyrophosphate that inhibit osteoclast activity and decrease boneturnover and resorption.

The bisphosphonates alendronic acid and risedronate sodium areconsidered the drugs of choice for treatment of osteoporosis, butdisodium etidronate may also be used. Treatment results in lowerfracture rates and higher bone density in both male and female patients.Lifestyle changes are also generally prescribed for sufferers.

Whilst it is known to treat osteoporosis with bisphosphonates, there area number of gastrointestinal symptoms associated with this class ofdrugs such as abdominal pain, dyspepsia, diarrhoea or constipation.Severe gastrointestinal reactions and oesophageal reactions such asoesophagitis, erosions, and ulceration have occurred. As a consequencebiphosphonates should not be administered to patients with abnormalitiesof the oesophagus or other factors that might delay oesophagealemptying, or those unable to stand, or sit upright for at least 30minutes (Martindale). Strict instructions are set out for taking thesedrugs, patients taking alendronate are instructed to take it on an emptystomach before food and to remain sitting upright without eating for atleast 30 minutes after taking the drug. Similar instructions, in somecase stricter, apply for other bisphosphonates.

The reason for these instructions is that alendronate and otherbisphosphonates can provoke severe oesophageal irritation. This can leadto reflux into the oesophagus and consequent ulceration, oesophagitis,heartburn and retrosternal pain, pain on swallowing and dysphagia. Inaddition to these side-effects, there is reduced patient compliance withthe bisphosphonate treatment, leading to progression of theosteoporosis.

Bisphosphonate treatment is so effective that it is very widely used.Patients have hitherto had to put up with the adverse symptomsassociated with bisphosphonate use as there is no alternative treatmentthat gives such good results.

An object of the invention is to ameliorate the above problems anddisadvantages. An object of a specific embodiment of the invention is toprovide a formulation of a bisphosphonate which provokes reduced gastricirritation and/or reduced reflux of stomach acid, leading preferably toincreased patient compliance.

SUMMARY OF THE INVENTION

Accordingly the present invention provides a pharmaceutical formulationcomprising a bisphosphonate and an antifoaming agent, and also providesfor administration of a bisphosphonate in combination with anantifoaming agent.

In use, for example in treatment of osteoporosis, the combination isexpected to limit the formation of foams in the stomach. Without wishingto be bound by any particular theory, it is believed that the associatedconcomitant decrease in the volume of stomach contents, and additionallybarrier properties of some preferred antifoaming agents, will reduce thelikelihood of stomach acid reflux and therefore oesophageal irritation.

The antifoaming agent may comprise an agent to lower surface tensionand/or to reduce the foaming tendency of stomach contents, and more thanone agent may be advantageously used in concert to reduce foaming, and,in preferred embodiments also provide barrier protection.

Antifoaming agents are known to those of skill in the art. Whilst manydifferent agents may be used in the formulations of the invention,presently there are only a limited number of approved antifoaming agentsavailable for pharmaceutical formulations, and these are particularlysuitable. Siloxanes can be used. Some embodiments use one or morepolydimethylsiloxanes as the antifoaming agent. Preferred embodiments ofthe formulation of the invention comprise dimethicone BP, simethicone BP(an activated form of dimethicone), or both. The terms “dimethicone” and“dimeticone” are used interchangeably herein. Also, the terms“simethicone” and “simeticone” are used interchangeably herein.

Any bisphosphonate having the side-effect of promoting gastricirritation may suitably be used in the formulations of the invention.The invention applies generally to formulations of bisphosphonates,including for example alendronic acid, disodium etidronate, disodiumpamidronate, ibandronic acid, risedronate sodium, sodium clodronate,strontium ranelate, tiludronic acid and zoledronic acid. In preferredembodiments the bisphosphonate may be selected from the group alendronicacid or alendronate, risedronate and etidronate. Particularly preferredformulations comprise alendronic acid or alendronate. Formulations ofthe invention comprise also a pharmaceutically acceptable carrier.

Bisphosphonates can be co-administered with other agents helpful intreatment of osteoporosis, either directly or dealing e.g. with sideeffects of the treatment. Formulations of the invention may thus alsoinclude one or more of a vitamin D derivative and a calcium supplement.

The term ‘Vitamin D derivative’ is used for a range of compounds whichhave the ability to prevent or treat rickets. Vitamin D supplementssuitable for inclusion in formulations of the invention includeergocalciferol (calciferol, vitamin D2), cholecalciferol (vitamin D3),dihydrotachysterol, alfacalcidol (1α-hydroxycholecalciferol), andcalcitriol (1,25-dihydroxycholecalciferol).

Some calcium supplements which may be used in the formulations of theinvention are calcium salts, optionally selected from calcium gluconate,calcium chloride, calcium lactate, ADCAL®, CACIT®, CALCICHEW®,CALCIUM-500®, CALCIUM-SANDOZ® and SANDOCAL®. Treatments of the inventionmay also be carried out in combination with parenteral calciumsupplements.

Particularly preferred formulations of the invention comprise abisphosphonate, antifoaming agent, a vitamin D derivative and a calciumsupplement.

Formulations of the invention include one or more agents to reducesurface tension and/or reduce the tendency of the stomach contents tofoam, and may also elicit barrier protection. Treatment according to theinvention involves the administration of one or more such agents withbisphosphonates simultaneously, either together (in the sameformulation) or separately (taken together at the same time), orseparately (time delayed administration).

Hence, the bisphosphonate and the antifoaming agent can be takenseparately. In these embodiments the antifoaming agent is generallytaken up to 1 hour before and not more than 10 minutes after thebisphosphonate. Preferably the antifoaming agent is taken not more than10 minutes before and more preferably not more than 5 minutes before thebisphosphonate.

In a further aspect the invention provides a kit including abisphosphonate and an antifoaming agent. Preferred kits include otheractives such as vitamin D derivatives and/or calcium supplements.

In another aspect the invention provides for the use of an antifoamingagent in the manufacture of a medicament for the treatment orprophylaxis of osteoporosis in combination with a bisphosphonate. Theinvention also provides for the use of a bisphosphonate in themanufacture of a medicament for the treatment or prophylaxis ofosteoporosis in combination with an antifoaming agent. Preferably thebisphosphonate is alendronate and the antifoaming agent is a siloxane.The medicament may advantageously contain other actives as outlinedherein.

For the purposes of the present specification the phrase ‘treatment orprophylaxis of osteoporosis’ means any and all treatment or prophylaxisfor Paget's disease, osteopenia, osteoporosis and corticosteroid-inducedosteoporosis.

The invention also provides methods for the treatment of osteoporosiscomprising administration to a patient of a bisphosphonate and anantifoaming agent.

The formulations, methods, kits and uses discussed offer potentialreduced mucosal irritation, gastric irritation and/or oesophagealirritation when compared to the art known bisphosphonate formulations.An anticipated advantage of the invention is hence that this irritationis reduced. Further anticipated advantages are that instructions topatients, which hitherto gave strict advice as to how to take themedicament, can be relaxed and lower irritation will naturally lead togreater patient compliance with the medication regime and greateroverall effectiveness of treatment.

EXAMPLES

Various aspects of the invention will now be described with reference tothe accompanying Examples. The examples are not to be construed aslimiting the scope of the invention as claimed herein. One of skill inthe pharmaceutical arts will understand that some of the ingredients ofthe formulations given in the examples may be substituted with knownequivalent ingredients. These formulations are within the scope of theinvention.

Example 1

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P.  50.0 mg Microcrystalline cellulose B.P. 140.0 mgLactose B.P. 110.0 mg Croscarmellose sodium B.P.  6.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica B.P.  1.0 mg Magnesiumstearate  2.0 mg Total 400.4 mg

Example 2

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Simeticone B.P.  50.0 mg Microcrystalline cellulose B.P. 140.0 mgCalcium carbonate B.P. 105.0 mg Povidone B.P  6.0 mg Croscarmellosesodium B.P.   5.0 mg. Dehydrated Alcohol USP q.s Colloidal anhydroussilica B.P.  1.0 mg Magnesium stearate  2.0 mg Total 400.4 mg

Example 3

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Simeticone B.P.  25.0 mg Dimethicone B.P.  25.0 mg Microcrystallinecellulose B.P. 140.0 mg Magnesium carbonate B.P. 110.0 mg Croscarmellosesodium B.P.  6.0 mg Dehydrated Alcohol USP q.s. Colloidal anhydroussilica B.P.  1.0 mg Magnesium stearate  2.0 mg Total 400.4 mg

Example 4

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P.  50.0 mg Microcrystalline cellulose B.P. 140.0 mgSucrose B.P. 110.0 mg Croscarmellose sodium B.P.  6.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica B.P.  1.0 mg Magnesiumstearate  2.0 mg Total 400.4 mg

Example 5

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P.  50.0 mg Microcrystalline cellulose B.P. 140.0 mgLactose B.P. 110.0 mg Croscarmellose sodium B.P.  6.0 mg IsopropylAlcohol USP q.s. Colloidal anhydrous silica B.P.  1.0 mg Magnesiumstearate  2.0 mg Total 400.4 mg

Example 6

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P.  50.0 mg Microcrystalline cellulose B.P. 140.0 mgLactose B.P. 110.0 mg Croscarmellose sodium B.P.  6.0 mg Purified Waterq.s. Colloidal anhydrous silica B.P.  1.0 mg Magnesium stearate  2.0 mgTotal 400.4 mg

Example 7

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P.  50.0 mg Microcrystalline cellulose B.P. 140.0 mgLactose B.P. 110.0 mg Croscarmellose sodium B.P.  6.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica B.P.  1.0 mg Stearic Acid 2.0 mg Total 400.4 mg

Example 8

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P. 100.0 mg Microcrystalline cellulose B.P. 280.0 mgLactose B.P. 113.0 mg Croscarmellose sodium B.P.  12.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica BP  2.0 mg Magnesiumstearate  3.0 mg Total 601.4 mg

Example 9

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Simeticone B.P. 100.0 mg Microcrystalline cellulose B.P. 280.0 mgLactose B.P. 113.0 mg Croscarmellose sodium B.P.  12.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica BP  2.0 mg Magnesiumstearate  3.0 mg Total 601.4 mg

Example 10

Alendronic acid 70 mg (as sodium 91.4 mg alendronate trihydrate)Dimeticone B.P. 50.0 mg Simeticone B.P. 50.0 mg Microcrystallinecellulose B.P. 280.0 mg  Lactose B.P. 113.0 mg  Croscarmellose sodiumB.P. 12.0 mg Dehydrated Alcohol USP q.s. Colloidal anhydrous silica BP 2.0 mg Magnesium stearate  3.0 mg Total 601.4 mg 

Example 11

Alendronic acid 70 mg (as sodium  91.4 mg alendronate trihydrate)Dimeticone B.P. 100.0 mg Microcrystalline cellulose B.P. 280.0 mgSucrose B.P. 113.0 mg Croscarmellose sodium B.P.  12.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica BP  2.0 mg Magnesiumstearate  3.0 mg Total 601.4 mg

Example 12

Alendronic acid 70 mg (as sodium 91.4 mg alendronate trihydrate)Dimeticone B.P. 100.0 mg Microcrystalline cellulose B.P. 280.0 mgLactose B.P. 113.0 mg Croscarmellose sodium B.P. 12.0 mg Isopropylalchol B.P. q.s. Colloidal anhydrous silica BP 2.0 mg Magnesium stearate3.0 mg Total 601.4 mg

Example 13

Alendronic acid 70 mg (as sodium 91.4 mg alendronate trihydrate)Dimeticone B.P. 100.0 mg Microcrystalline cellulose B.P. 280.0 mgLactose B.P. 113.0 mg Croscarmellose sodium B.P. 12.0 mg Purified waterB.P. q.s. Colloidal anhydrous silica BP 2.0 mg Magnesium stearate 3.0 mgTotal 601.4 mg

Example 14

Alendronic acid 70 mg (as sodium 91.4 mg alendronate trihydrate)Dimeticone B.P. 100.0 mg Microcrystalline cellulose B.P. 280.0 mgLactose B.P. 113.0 mg Croscarmellose sodium B.P. 12.0 mg DehydratedAlcohol USP q.s. Colloidal anhydrous silica BP 2.0 mg Stearic acid 3.0mg Total 601.4 mg

Example 15

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Dimeticone B.P. 50.0 mg Microcrystalline cellulose B.P. 140.0 mg LactoseB.P. 80.0 mg Croscarmellose sodium B.P. 6.0 mg Dehydrated Alcohol USPq.s Colloidal anhydrous silica BP 1.0 mg Magnesium stearate 2.0 mg Total292.1 mg

Example 16

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Simeticone B.P. 50.0 mg Microcrystalline cellulose B.P. 140.0 mg LactoseB.P. 80.0 mg Croscarmellose sodium B.P. 6.0 mg Dehydrated Alcohol USPq.s Colloidal anhydrous silica BP 1.0 mg Magnesium stearate 2.0 mg Total292.1 mg

Example 17

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Simeticone B.P. 25.0 mg Dimeticone B.P. 250.0 mg Microcrystallinecellulose B.P. 140.0 mg Lactose B.P. 80.0 mg Croscarmellose sodium B.P.6.0 mg Dehydrated Alcohol USP q.s Colloidal anhydrous silica BP 1.0 mgMagnesium stearate 2.0 mg Total 292.1 mg

Example 18

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Dimeticone B.P. 50.0 mg Microcrystalline cellulose B.P. 140.0 mg SucroseB.P. 80.0 mg Croscarmellose sodium B.P. 6.0 mg Dehydrated Alcohol USPq.s Colloidal anhydrous silica BP 1.0 mg Magnesium stearate 2.0 mg Total292.1 mg

Example 19

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Dimeticone B.P. 50.0 mg Microcrystalline cellulose B.P. 140.0 mg LactoseB.P. 80.0 mg Croscarmellose sodium B.P. 6.0 mg Isopropyl Alcohol USP q.sColloidal anhydrous silica BP 1.0 mg Magnesium stearate 2.0 mg Total292.1 mg

Example 20

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Dimeticone B.P. 50.0 mg Microcrystalline cellulose B.P. 140.0 mg LactoseB.P. 80.0 mg Croscarmellose sodium B.P. 6.0 mg Purified water q.sColloidal anhydrous silica BP 1.0 mg Magnesium stearate 2.0 mg Total292.1 mg

Example 21

Alendronic acid 10 mg (as sodium 13.1 mg alendronate trihydrate)Dimeticone B.P. 50.0 mg Microcrystalline cellulose B.P. 140.0 mg LactoseB.P. 80.0 mg Croscarmellose sodium B.P. 6.0 mg Dehydrated Alcohol USPq.s Colloidal anhydrous silica BP 1.0 mg Stearic Acid 2.0 mg Total 292.1mg

The formulations of Examples 1-21 are manufactured according to thefollowing manufacturing examples:

Example 22

To manufacture tablet formulations of the above examples the dryingredients 1-5 (dry ingredients 1-6 in examples 3, 10 and 17 where bothsimeticone and dimeticone are included) are mixed together. Item 6 (item7 for examples 3, 10 and 17) is then added to form a wet granulatesuitable for compression. The wet granulate is then dried and milled togive a uniform granule. The dry milled granules are then mixed withexcipients 7 & 8 and compressed to a suitable hardness.

Example 23

Tablets are prepared as above (example 22) but item 2 is omitted fromthe dry mix and then added to the solvent, i.e. item 6 (or 7), prior toit being added to the dry mix of ingredient. The remaining steps are thesame as for example 22.

Example 24

Tablets are prepared as above for example 22 but item 6 (or 7), thesolvent of granulation, is omitted and the product is manufactured bydirect compression.

Example 25

Ingredients 1-5 (or 1-6) are dry mixed followed by dry milling. Theremaining excipients are then blended into the dry ingredients and theresultant mass is compressed to a suitable hardness to give tablets orencapsulated into a suitably sized capsule.

Example 26

A tablet is made in which simeticone granules are manufacturedseparately and then blended with the other ingredients.

1. Simeticone B.P. 100.0 mg 2. Mannitol B.P. 400.0 mg 3. Povidone B.P.6.0 mg 4. Sodium starch glycollate B.P. 12.0 mg 5. Purified Water B.Pq.s sub total 518.0 mg

To make the simeticone granules items 1-4 are dry mixed, water is addedand then the mixture is wet mixed. The mixture is then dried and milledto give a uniform granule.

A. Alendronic acid 70 mg (as sodium 91.4 mg alendronate trihydrate) B.Simethicone granule 259.0 mg C. Purified Talc B.P. 18.0 mg D. StearicAcid B.P. 6.0 mg Total 374.4 mg

The required amount of simeticone granules (in this particular case259.0 mg) are then mixed with ingredients A, C and D until a uniformmixture is obtained. The mixture is then compressed to a suitablehardness to give tablets.

Example 27

Tablets are prepared as for the method of Example 26 except that theamounts of items B-D are doubled to give a tablet containing 100 mgsimeticone with a tablet compression weight of 633.36 mg.

Example 28

Tablets are prepared as for the method of Example 26 except initiallyusing half amounts of ingredients C & D before dry granulation. Thecompacted granule is then milled and the remainder of items C & D added.The final mix is then blended and compressed to a suitable hardness togive tablets.

Example 29

1. Etidronate sodium 200.0 mg 2. Simeticone B.P. 50.0 mg 3. Maize starchB.P. 20.0 mg 4. Microcrystalline cellulose 100.0 mg 5. Purified waterq.s 6. Maize starch 30.0 mg 7. Colloidal anhydrous silica 1.5 mg 8.Magnesium stearate 7.0 mg Total 408.5 mg

Items 1 & 4 are dry mixed and then item 2 is slowly added untildispersed. A small quantity of water is then added followed by theetidronate disodium. The ingredients are mixed until well dispersed andadditional water is added to form a wet granule suitable forcompression. The wet granule is then dried and milled and the remainingitems are added. The mixture is then compressed at a suitable hardnessor encapsulate into a size 1 capsule.

Example 30

Tablets are prepared as for example 26 but alendronate is separatelyreplaced with (a) 35 mg of risedronic acid, (b) 400 mg of sodiumclodronate, and (c) 200 mg of tiludronic acid.

Examples 31-41

Ingredient (mg) 31 32 33 34 Biphosphonate⁺ Q.S Q.S Q.S Q.S SimethiconeUSP 55.0 110.0 55.0 Dimethicone NF 50.0 — — Mannitol 300.0 270.0 320.0300.0 Polyvidone 3.5 3.5 14.0 — Maize Starch 8.0 — Pregelatinised — 25.070.0 40.0 Starch Microcrystalline 130.0 115.0 120.0 80.0 cellulose L-HPC20.0 32.0 30.0 30.0 Sodium 5.0 8.0 18.0 — croscarmellose Silicon dioxide5.0 — — Sodium stearyl — — 5.0 fumarate Total 521.5 mg 508.5 mg 682.0 mg510.0 mg Ingredient (mg) 35 36 37 38 Biphosphonate⁺ q.s q.s q.s q.sSimethicone USP 55.0 55.0 Dimethicone NF 50.0 100.0 — Lactose hydrous300.0 360.0 300.0 — Lactose anhydrous — — Mannitol — 250.0 Polyvidone3.5 — 20.0 — Gelatin. — 18.0 Maize Starch 8.0 60.0 — 7.0 Pregelatinised— — — — Starch Microcrystalline 120.0 100.0 100.0 125.0 cellulose L-HPC20.0 20.0 30.0 30.0 Sodium — 10.0 18.0 15.0 croscarmellose Ph.EurCrospovidone 10.0 — — Silicon dioxide 5.0 10.0 — Sodium stearyl — 5.05.0 fumarate Total 516.5 mg 683.0 mg 523.0 mg 487.0 mg ⁺The therapeuticdose of the biphosphonate.

-   -   Capsules

Ingredient (mg) 39 40 41 Biphosphonate⁺ q.s q.s q.s Simethicone USP110.0 55.0 110.0 Lactose hydrous 180.0 Lactose anhydrous Mannitol 200.0150.0 Gelatin. — — 15.0 Maize Starch 20.0 Pregelatinised — 20.0 StarchMicrocrystalline 30.0 65.0 30.0 cellulose L-HPC 10.0 10.0 Sodium 5.0 5.015.0 croscarmellose Ph.Eur Crospovidone — 10.0 Total 375.0 mg 305 mg360.0 mg

The invention thus provides formulations and uses thereof for treatmentof osteoporosis with reduced gastric and other irritation.

Although the invention has been described with reference to specificexamples one of skill in the art will appreciate that variations may bemade to these formulations without departing from the scope of thefollowing claims.

1.-35. (canceled)
 36. A method of reducing foam formation in a patient'sstomach in response to administration of a bisphosphonate-containingcomposition, comprising administering to the patient thebisphosphonate-containing composition in combination with an amount ofan antifoaming agent effective to reduce foam formation, therebyreducing formation of foam in the patient's stomach.
 37. The method ofclaim 36, wherein the amount of antifoaming agent is in the range of 20mg to 150 mg.
 38. The method of claim 36, wherein the amount ofantifoaming agent is in the range of 35 mg to 125 mg.
 39. The method ofclaim 36, wherein the amount of antifoaming agent is in the range of 3%to 40% by weight of the bisphosphonate-containing composition.
 40. Themethod of claim 36, wherein the amount of antifoaming agent is in therange of 5% to 30% by weight of the bisphosphonate-containingcomposition.
 41. The method of claim 36, wherein the antifoaming agentis one or more polydimethylsiloxanes.
 42. The method of claim 41,wherein the antifoaming agent comprises dimethicone BP.
 43. The methodof claim 41, wherein the antifoaming agent comprises simethicone BP. 44.The method of claim 36, wherein the bisphosphonate-containingcomposition additionally includes an antacid.
 45. The method of claim36, wherein the bisphosphonate is selected from the group consisting ofalendronic acid, disodium etidronate, disodium pamidronate, ibandronicacid, risedronate sodium, sodium clodronate, strontium ranelate,tiludronic acid, and zoledronic acid.
 46. The method of claim 36,wherein the bisphosphonate-containing composition additionally comprises(i) a vitamin D derivative, (ii) a calcium supplement, or (iii) both (i)and (ii).
 47. The method of claim 36, wherein thebisphosphonate-containing composition additionally comprises apharmaceutically acceptable carrier selected from the group consistingof one or more of microcrystalline cellulose, lactose, croscarmellosesodium, colloidal anhydrous silica, magnesium stearate, calciumcarbonate, povidone, sucrose, stearic acid, sodium starch glycollate,talc, maize starch, mannitol, pregelatinized starch, low-substitutedhydroxypropyl cellulose, silicon dioxide, sodium stearyl fumarate,gelatin, and crospovidone.
 48. A method of reducing foam formation in apatient's stomach in response to administration of abisphosphonate-containing composition, comprising administering to thepatient the bisphosphonate-containing composition in combination withfrom 35 mg to 125 mg of an antifoaming agent selected from simethicone,dimethicone, and mixtures thereof, thereby reducing formation of foam inthe patient's stomach.
 49. The method of claim 48, wherein thebisphosphonate is selected from the group consisting of alendronic acid,disodium etidronate, disodium pamidronate, ibandronic acid, risedronatesodium, sodium clodronate, strontium ranelate, tiludronic acid, andzoledronic acid.
 50. The method of claim 48, wherein thebisphosphonate-containing composition additionally comprises (i) avitamin D derivative, (ii) a calcium supplement, or (iii) both (i) and(ii).
 51. A method of reducing foam formation in a patient's stomach,reducing stomach acid reflux and reducing esophageal irritation inresponse to administration of a bisphosphonate, comprising administeringto the patient a formulation comprising the bisphosphonate, apharmaceutically acceptable carrier and an antifoaming agent selectedfrom simethicone, dimethicone, and mixtures thereof, wherein the amountof antifoaming agent administered is in the range of from 5% to 30% byweight of the formulation, thereby reducing foam formation, stomach acidreflux, and esophageal irritation.
 52. The method of claim 51, whereinthe bisphosphonate is selected from the group consisting of alendronicacid, disodium etidronate, disodium pamidronate, ibandronic acid,risedronate sodium, sodium clodronate, strontium ranelate, tiludronicacid, and zoledronic acid.
 53. The method of claim 51, wherein theantifoaming agent is administered in the range of from 7% to 18% byweight of the formulation.
 54. The method of claim 51, wherein thebisphosphonate-containing composition additionally comprises apharmaceutically acceptable carrier selected from the group consistingof one or more of microcrystalline cellulose, lactose, croscarmellosesodium, colloidal anhydrous silica, magnesium stearate, calciumcarbonate, povidone, sucrose, stearic acid, sodium starch glycollate,talc, maize starch, mannitol, pregelatinized starch, low-substitutedhydroxypropyl cellulose, silicon dioxide, sodium stearyl fumarate,gelatin, and crospovidone.